Tumor progression in colorectal carcinoma is marked by several clinically distinct stages. Hyperplasia of the colon crypt mucosa is followed by adenoma formation, then adenocarcinoma and, finally, metastatic disease. The molecular genetic events underlying these events in tumor progression have begun to be elucidated. Activation of the ras oncogene and loss of function of the p53, DCC and APC genes are strongly associated with progression at specific stages. The latter three genes, all tumor suppressor or candidates, were identified initially due to observable chromosome abnormalities and/or loss of heterozygosity (LOH) of specific alleles in the tumor cells of colon cancer patients. Inherited mutations in these genes greatly enhance the probability of developing neoplasms at some time. However, most of the more than 130,000 cases of colon cancer that will develop this year will do so without any early indication, such as inherited mutation. Subtractive cDNA hybridization has been utilized to isolate cDNAs for which there is no a priori information, such as LOH, but which are differentially regulated in normal and tumor cells. Several genes have been identified which are differentially regulated. Some of these are previously uncloned and unknown genes. One of them, called DRA, for down- regulated in adenoma, has been extensively studied and characterized. It is a possible tumor-suppressor gene and it is highly tissue specific.